Review of 5-FU resistance mechanisms in colorectal cancer: clinical significance of attenuated on-target effects

Cancer Drug Resistance, Journal Year: 2023, Volume and Issue: 6(2), P. 257 - 272

Published: Jan. 1, 2023

The emergence of chemoresistant disease during chemotherapy with 5-Fluorouracil-based (5-FU-based) regimens is an important factor in the mortality metastatic CRC (mCRC). causes 5-FU resistance are multi-factorial, and besides DNA mismatch repair deficiency (MMR-D), there no widely accepted criteria for determining which patients not likely to be responsive 5-FU-based therapy. Thus, a need systematically understand mechanistic basis treatment failure urgent develop new approaches circumventing major resistance. In this manuscript, we review mechanisms emphasis on: (1) altered anabolic metabolism limiting formation primary active metabolite Fluorodeoxyuridylate (5-Fluoro-2'-deoxyuridine-5'-O-monophosphate; FdUMP); (2) elevated expression or activity enzymatic target thymidylate synthase (TS); (3) dysregulated programmed cell death as Importantly, these can potentially overcome through use next-generation fluoropyrimidine (FP) polymers (e.g., CF10) that display reduced dependence on more potent TS inhibitory activity.

Language: Английский

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ABCB1 overexpression through locus amplification represents an actionable target to combat paclitaxel resistance in pancreatic cancer cells

Journal of Experimental & Clinical Cancer Research, Journal Year: 2024, Volume and Issue: 43(1)

Published: Jan. 2, 2024

Abstract Background Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest types cancer and chemotherapies such as gemcitabine/nab-paclitaxel are confronted with intrinsic or acquired resistance. The aim this study was to investigate mechanisms underlying paclitaxel resistance in PDAC explore strategies overcome it. Methods Three (PR) gemcitabine resistant (GR) models were established. Transcriptomics proteomics used identify conserved drug Genetic pharmacological approaches Results Upregulation ABCB1 through locus amplification identified a feature unique PR cells. not affected any GR no cross observed. inhibitor verapamil siRNA-mediated depletion sensitized cells prevented efflux substrates all models. expression associated trend towards shorter survival patients who had received treatment. A screen known novel kinase inhibitors that attenuate sensitize paclitaxel. Conclusion represents novel, mechanism Kinase can be further (pre) clinically explored therapeutic PDAC.

Language: Английский

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Antibody–drug conjugates in cancer therapy: mechanisms and clinical studies

MedComm, Journal Year: 2024, Volume and Issue: 5(8)

Published: July 28, 2024

Abstract Antibody–drug conjugates (ADCs) consist of monoclonal antibodies that target tumor cells and cytotoxic drugs linked through linkers. By leveraging antibodies’ targeting properties, ADCs deliver into via endocytosis after identifying the antigen. This precise method aims to kill selectively while minimizing harm normal cells, offering safe effective therapeutic benefits. Recent years have seen significant progress in antitumor treatment with ADC development, providing patients new potent options. With over 300 explored for various indications some already approved clinical use, challenges such as resistance due factors like antigen expression, processing, payload emerged. review outline history their structure, mechanism action, recent composition advancements, selection, completed ongoing trials, mechanisms, intervention strategies. Additionally, it will delve potential novel markers, linkers, payloads, innovative action mechanisms enhance cancer The evolution has also led emergence combination therapy a approach improve drug efficacy.

Language: Английский

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Advances in Light-Responsive Smart Multifunctional Nanofibers: Implications for Targeted Drug Delivery and Cancer Therapy

Pharmaceutics, Journal Year: 2024, Volume and Issue: 16(8), P. 1017 - 1017

Published: July 31, 2024

Over the last decade, scientists have shifted their focus to development of smart carriers for delivery chemotherapeutics in order overcome problems associated with traditional chemotherapy, such as poor aqueous solubility and bioavailability, low selectivity targeting specificity, off-target drug side effects, damage surrounding healthy tissues. Nanofiber-based systems recently emerged a promising system cancer therapy owing unique structural functional properties, including tunable interconnected porosity, high surface-to-volume ratio entrapment efficiency loading capacity, mass transport which allow controlled targeted delivery. In addition, they are biocompatible, biodegradable, capable surface functionalization, allowing target-specific release. One most common fiber production methods is electrospinning, even though relatively two-dimensional (2D) tightly packed structures rates limited its performance. Forcespinning an alternative spinning technology that generates high-throughput, continuous polymeric nanofibers 3D structures. Unlike forcespinning fibers by centrifugal forces rather than electrostatic forces, resulting significantly higher production. The functionalization nanocarriers on can result anticancer capabilities be activated external stimuli, light. This review addresses current trends potential applications light-responsive dual-stimuli-responsive electro- forcespun therapy, particular emphasis functionalizing nanofiber surfaces developing nano-in-nanofiber emerging dual-controlled release high-precision tumor targeting. progress prospective diagnostic therapeutic discussed context combination therapy.

Language: Английский

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Applications of nanofibers drug delivery system in cancer therapy

Journal of Drug Delivery Science and Technology, Journal Year: 2023, Volume and Issue: 90, P. 105128 - 105128

Published: Nov. 2, 2023

Language: Английский

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Localized Therapeutic Approaches Based on Micro/Nanofibers for Cancer Treatment

Molecules, Journal Year: 2023, Volume and Issue: 28(7), P. 3053 - 3053

Published: March 29, 2023

Cancer remains one of the most challenging health problems worldwide, and localized therapeutic approaches based on micro/nanofibers have shown potential for its treatment. Micro/nanofibers offer several advantages as a drug delivery system, such high surface area, tunable pore size, sustained release properties, which can improve efficacy reduce side effects. In addition, functionalization these fibers with nanoparticles enhance their targeting capabilities. Localized drugs and/or other agents via also help to overcome limitations systemic administration, poor bioavailability off-target Several studies promising results in preclinical models cancer, including inhibition tumor growth improved survival rates. However, more research is needed technical regulatory challenges bring clinical use. hold great promise future cancer treatment, providing targeted, effective, minimally invasive alternative traditional treatments. The main focus this review explore current treatments utilizing micro/nanofibers, well systems that rely fibrous structures deliver treatment specific area.

Language: Английский

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Downregulation of ABCC3 activates MAPK signaling through accumulation of deoxycholic acid in colorectal cancer cells

Cancer Science, Journal Year: 2024, Volume and Issue: 115(6), P. 1778 - 1790

Published: April 2, 2024

Abstract ABCC3 (also known as MRP3) is an ATP binding cassette transporter for bile acids, whose expression downregulated in colorectal cancer through the Wnt/β‐catenin signaling pathway. However, it remained unclear how downregulation of contributes to carcinogenesis. We explored role progression cancer—in particular, focusing on regulation acid export. Gene analysis adenoma isolated from familial adenomatous polyposis patients revealed that genes related secretion including were early at stage formation. Knockdown or overexpression increased decreased intracellular concentration deoxycholic acid, a secondary respectively, cells. Forced suppressed acid‐induced activation MAPK signaling. Finally, we found nonsteroidal anti‐inflammatory drugs cells, suggesting could be one targets therapeutic intervention polyposis. Our data thus suggest carcinogenesis accumulation acids and activity

Language: Английский

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Dysregulation of a Subset of Circulating and Vesicle-Associated miRNA in Pancreatic Cancer

Non-Coding RNA, Journal Year: 2024, Volume and Issue: 10(3), P. 29 - 29

Published: May 1, 2024

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive neoplasia, characterized by early metastasis, low diagnostic rates at stages, resistance to drugs, and poor prognosis. There an urgent need better characterize this disease in order identify efficient diagnostic/prognostic biomarkers. Since microRNAs (miRNAs) contribute oncogenesis metastasis formation PDAC, they are considered potential candidates for fulfilling task. In work, levels two miRNA subsets (involved chemoresistance or with oncogenic/tumor suppressing functions) were investigated a panel PDAC cell lines liquid biopsies small cohort patients. We used RT-qPCR droplet digital PCR (ddPCR) measure amounts cellular- vesicle-associated, circulating miRNAs. found that both lines, also after gemcitabine treatment, patients showed cellular-and vesicle-associated miR-155-5p, compared controls. Interestingly, we did not find any differences when analyzed miR-155-5p. Furthermore, vesicle-related miR-27a-3p increased cancer controls, while let-7a-5p, miR-221-3p, miR-23b-3p miR-193a-3p presented as dysregulated healthy individuals. Our results highlight clinical significance these miRNAs non-invasive molecular tools PDAC.

Language: Английский

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Potential role of thymoquinone to treat gastrointestinal cancers: insights into its molecular mechanisms

Naunyn-Schmiedeberg s Archives of Pharmacology, Journal Year: 2025, Volume and Issue: unknown

Published: March 5, 2025

Language: Английский

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Relevance of transportome among the mechanisms of chemoresistance in hepatoblastoma

Biochemical Pharmacology, Journal Year: 2025, Volume and Issue: unknown, P. 116914 - 116914

Published: April 1, 2025

Approximately 20 % of hepatoblastomas (HBs) exhibit a poor response to conventional chemotherapy due mechanisms chemoresistance (MOCs), such as reduced intracellular drug accumulation. This study evaluated the role transportome in multidrug resistance (MDR) HB. Paired HB and adjacent liver tissue samples (n = 19) HB-derived cell lines (HepG2, HuH6) were analyzed for their resistome characterization at mRNA (RT-qPCR, Taqman Low-Density Array, sequencing) protein (western blot, immunohistochemistry, immunofluorescence) levels. Cell viability (MTT test) proliferation migration (holographic microscopy) determined. The impact short-term (72 h) long-term (>10 months) exposure cells cisplatin or doxorubicin on was investigated. Solute carrier (SLC) family transporters showed minor relevance MDR, while export pumps, particularly MRP2, associated with chemotherapy. Exposure upregulated MDR1, MRP1 MRP2. In induced persistent chemoresistance, expression genes involved other MOCs, epigenetic machinery altered. Chemoresistant cross-resistance several anticancer drugs but maintained sensitivity cabozantinib. conclusion, not SLC uptake transporters, are key contributors chemoresistance. Cabozantinib emerges potential therapeutic option tumors resistant

Language: Английский

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